Mutant allele knockout with novel CRISPR nuclease promotes myelopoiesis in ELANE neutropenia.

Severe congenital neutropenia (SCN) is a life-threatening marrow failure disorder, usually caused by heterozygous mutations in . Potential genetic treatment strategies include biallelic knockout or gene correction via homology-directed repair (HDR). Such strategies, however, involve the potential loss of the essential function of the normal allele product or limited coverage of diverse monogenic mutations within the patient population, respectively.

Refinement of the endogenous epitope tagging technology allows the identification of a novel NRAS binding partner in melanoma.

The NRAS oncoprotein is highly mutated in melanoma. However, to date, no comprehensive proteomic study has been reported for NRAS. Here, we utilized the endogenous epitope tagging (EET) approach for the identification of novel NRAS binding partners.

RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells.

Analysis of 501 melanoma exomes revealed RGS7, which encodes a GTPase-accelerating protein (GAP), to be a tumor-suppressor gene. RGS7 was mutated in 11% of melanomas and was found to harbor three recurrent mutations (p.R44C, p.

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies.

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body.

Recurrent inactivating RASA2 mutations in melanoma.

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival.

YAP and the drug resistance highway.

Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target.

A highly recurrent RPS27 5'UTR mutation in melanoma.

The incidence of melanoma continues to rise globally and is increasing at a rate greater than any other cancer. To systematically search for new genes involved in melanomagenesis, we collated exome sequencing data from independent melanoma cohort datasets, including those in the public domain. We identified recurrent mutations that may drive melanoma growth, survival or metastasis, and which may hold promise for the design of novel therapies to treat melanoma.

Modulation of drug resistance in ovarian adenocarcinoma using chemotherapy entrapped in hyaluronan-grafted nanoparticle clusters.

Resistance to anticancer drugs is considered a major cause of chemotherapy failure. One of the major mediators of resistance is the multidrug extrusion pump protein, P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter with broad substrate specificity. In order to bypass this drug resistance mechanism, we have devised phospholipid-based nanoparticle clusters coated with the glycosaminoglycan hyaluronan, the major ligand of CD44, which is upregulated and undergoes different splice variations in many types of cancer cells.

eIF3c: a potential therapeutic target for cancer.

Cancer cells are rapidly evolving due to their unstable genome, which contributes to the development of new cancer clones with different gene expression profile (GEP). Manipulating the expression of the genes vital for the progression of the disease is essential to overcome its heterogeneity. However, targeting overexpressed genes, retrieved from GEP analysis, would be efficient for a specific kind of a malignancy.

RNA inhibition highlights cyclin D1 as a potential therapeutic target for mantle cell lymphoma.

Mantle cell lymphoma is characterized by a genetic translocation results in aberrant overexpression of the CCND1 gene, which encodes cyclin D1. This protein functions as a regulator of the cell cycle progression, hence is considered to play an important role in the pathogenesis of the disease. In this study, we used RNA interference strategies to examine whether cyclin D1 might serve as a therapeutic target for mantle cell lymphoma.

Identification of CTCF as a master regulator of the clustered protocadherin genes.

The brain is a large and complex network of neurons. Specific neuronal connectivity is thought to be based on the combinatorial expression of the 52 protocadherins (Pcdh) membrane adhesion proteins, whereby each neuron expresses only a specific subset. Pcdh genes are arranged in tandem, in a cluster of three families: Pcdhα, Pcdhβ and Pcdhγ.